The AT1 angiotensin II receptor (AT1R) is a typical G protein-coupled receptor (GPCR) and mediates the known physiological actions of the pressor octapeptide hormone, angiotensin II. It is also a significant factor in the development of hypertension and other cardiovascular diseases. Many of the intracellular actions of the AT1-R are dependent on its coupling to Gq/11 proteins, and activation of phosphoinositide-calcium signaling and phosphorylation cascades that regulate cell growth, differentiation and function. Several of these actions of Ang II are mediated by transactivation of receptor tyrosine kinases, in particular the EGF receptor (EGF-R), followed by activation of ras-dependent stimulation of MAP kinases. In the C9 hepatic cell line, the majority of Ang II-induced ERK phosphorylation is dependent on transactivation of the EGF-R, as described below. The ability of certain GPCRs to activate MAP kinase has been proposed to be dependent on their agonist-induced phosphorylation, recruitment of arrestins, and clathrin-mediated endocytosis. However, studies on normal and mutant AT1 receptors expressed in C9 and COS cells revealed that Ang II-induced ERK1/2 activation is independent of both AT1-R and EGF-R endocytosis, and is mediated by transactivation of the EGF-R. These and other studies have suggested that the dependence of MAP kinase activation on receptor endocytosis is confined to a minority of the GPCR family. The ability of several agonist-activated GPCRs to stimulate MAP kinase activity and growth responses is mediated by a variety of intracellular pathways, including transactivation of growth factor receptors and their downstream signaling cascades to the nucleus. Our recent studies on agonist activation of endogenous AT1 receptors expressed in hepatic C9 cells revealed that angiotensin-stimulated phosphoinositide hydrolysis, activation of PKCd, and phosphorylation of the proline-rich tyrosine kinase, Pyk-2, were associated with phosphorylation and activation of ERK1/2. These and related findings have demonstrated that Ang II increased the association of Pyk2 with Src and with the EGF receptor (EGF-R), and that the majority of Ang II-induced ERK phosphorylation is dependent on transactivation of the EGF-R. In these hepatic cells, Ang II-induced ERK activation is initiated by a PKCdelta-dependent but Ca2+-independent mechanism, and is predominantly mediated by the Src/Pyk2 complex through transactivation of the EGF-R. Further investigations are addressing the nature of the interactions between GPCRs and receptor tyrosine kinases, and the extent to which caveolae and other cell membrane structures are involved in the signaling cross-talk between different types of receptors expressed at the cell surface. Such studies are also in progress to evaluate the mechanisms and pathways that mediate the stimulation of MAP kinase responses in hypothalamic neuronal cells during activation of endogenous receptors for neurotransmitters, peptide hormones and growth factors. During agonist-induced endocytosis of the AT1-R and many other GPCRs, invagination of clathrin-coated pits and vesicle formation is dependent on the recruitment of the 100 kDa GTPase, dynamin, and several other accessory proteins. An analysis of the roles of the functional domains of dynamin in endocytosis of the AT1-R revealed that, similar to the recruitment of dynamin-1 during recycling of synaptic vesicles, interaction of the proline-rich domain of dynamin-2 with SH3 domains of amphiphysins and endophilins is essential for agonist-induced internalization of the AT1 receptor. This mechanism could be of general importance in the dynamin-dependent endocytosis of other GPCRs in non-neural tissues. In related studies on the endocytosis and processing of the AT1-R, utilizing a GFP-tagged receptor expressed in HEK cells, two phases of the internalization and recycling of the receptor to the cell membrane were identified. The internalized AT1 receptors are processed via vesicles that resemble multivesicular bodies, and return to the cell surface by a rapid, PI 3 kinase-dependent recycling pathway, and also by a slower pathway that is less sensitive to inhibition of PI 3-kinase.